Waldmann co-discovered the cytokine IL-15 and elucidated its role in the development of NK cells and CD8 memory phenotype T-cells. He demonstrated that IL-15 acts as a cell-membrane associated molecule, that IL-15R alpha on antigen-presenting cells (APCs) presents IL-15 in trans to NK and CD8 T-cells. Waldmann demonstrated IL-15 to be of value in 4 murine models of neoplasia. IL-15 administered by continuous intravenous infusion (CIV) at 20 mcg/kg for 10 days to rhesus macaques was associated with an 80-100-fold increase in the number of circulating CD8 effector memory T-cells. With Kevin Conlon Waldmann executed and reported a first-in-human phase I study of bolus administration of intravenous rhIL-15 in adults with refractory metastatic malignant melanoma and metastatic renal cell cancer. Five of 18 patients manifested a decrease in marker lesions, with 2 having clearing of lung lesions. A collaborative trial with the Cancer Immunotherapy Network (CITN) of subcutaneous Escherichia coli rhIL-15 has been completed where the MTD was 3 mcg/kg/day. Nineteen patients were enrolled at escalating doses with a profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8 T-cells with a maximal 3-fold expansion. An additional trial with continuous intravenous infusion of IL-15 had an MTD of 2 mcg/kg/day. Following the termination of CIV administration there was a 30-fold increase in the number of circulating NK cells and an over 350-fold increase in the number of CD56bright NK cells that were shown to be quite effective at antibody-dependent cellular cytotoxicity (ADCC), NKG2D/MIC and natural cytotoxicity. A particular challenge with rhIL-15 is that there is low-level expression of IL-15Ralpha on antigen-presenting cells including DCs. To address this issue, IL-15 and IL-15R alpha combination is being evaluated in a clinical trial. A major conclusion is that for IL-15 to be effective it will have to be used in combination therapy with other agents. To take advantage of our observation that IL-15 dramatically increases the number of circulating activated NK cells, a very attractive antitumor strategy is to use IL-15 in conjunction with antitumor monoclonal antibodies to augment their ADCC. In one syngeneic model EL4 leukemic cells were transfected with human CD20 and administered intravenously to immunologically intact mice. Mice treated with either IL-15 or rituximab (anti-CD20) alone showed modest efficacy. This efficacy was markedly augmented when the two agents were administered together. In a second xenograft model SCID/NOD mice bearing the MET-1 ATL leukemia receiving either alemtuzumab (CAMPATH) or IL-15 alone had only modest efficacy that was markedly augmented by the combination of IL-15 plus alemtuzumab. This efficacy was lost in FcRgamma delete mice supporting the hypothesis that its efficacy was due to ADCC. In additional studies, we demonstrated that both NK cells and macrophages are needed for optimal tumor clearance mediated by the combination of IL-15 and rituximab. In a working model of innate recognition, NK cells were induced by IL-15 to express NKG2D and macrophages to express the partner Rea-1 during antitumor immune responses, thus IL-15 activated macrophages license NK cells to perform ADCC. These observations have been translated by the initiation of a clinical trial involving alemtuzumab plus IL-15 for patients with ATL. A trial is being initiated in patients with refractory and relapsed CLL with obinutuzumab plus IL-15. In addition to translate preclinical studies, a trial is being initiated using IL-15 in combination with anti-CTLA-4 and anti-PD-L1. Furthermore, to translate the observation of increase in activated CD8 T-cells the combination of IL-15 with an agonistic anti-CD40 monoclonal antibody has shown augmented tumor antigen specific CD8 T-cells and increased tumor efficacy. Sckisel and coworkers demonstrated that the administration of a gamma cytokine (e.g., IL-15) leads to paralysis of CD4 but not CD8 T-cells that was mediated through transient expression of suppressor of cytokine signaling-3 (SOCS3). This paralysis of CD4 cells leads to a lack of required help for cytotoxic CD8 T-cells. The generation of helpless CD8 T-cells can be avoided by the administration of an agonistic anti-CD40 antibody. In our studies the combination of IL-15 with an agonistic CD40 antibody demonstrated synergy in the TRAMP-C2 prostatic cancer model. In this model the combination was associated with a marked increase in the number of TRAMP-C2 tumor-specific SPAS-1/SNC9-H8, tetramer positive CD8 T-cells. This observation is being translated into a clinical trial using optimized anti-CD40 monoclonal antibody plus IL-15 in patients with metastatic malignancy. In an additional study in a clinical trial previously we demonstrated a putative gain of function CCR4 mutation in 26% of adult T-cell leukemia (ATL) cells. Furthermore, over 95% of ATL cells express CCR4. To translate this observation, an anti-CCR4 CAR has been generated and will be utilized in clinical trials of patients with ATL and those with cutaneous T-cell lymphoma.